Guanidine and amidine derivatives as factor Xa inhibitors

ABSTRACT

The present invention relates to compounds of the formula I,  
                 
 
in which R 0 ; Q; X; Q′, D, R 10  and V have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can in general be applied in conditions in which an undesired activity of factor Xa and/or factor VIIa is present or for the cure or prevention of which an inhibition of factor Xa and/or factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

The present invention relates to compounds of the formula I,

in which R₀; Q; X; Q′, D, R₁₀ and V have the meanings indicated below.The compounds of the formula I are valuable pharmacologically activecompounds. They exhibit a strong antithrombotic effect and are suitable,for example, for the therapy and prophylaxis of cardiovascular disorderslike thromboembolic diseases or restenoses. They are reversibleinhibitors of the blood clotting enzymes factor Xa (FXa) and/or factorVIIa (FVIIa), and can in general be applied in conditions in which anundesired activity of factor Xa and/or factor VIIa is present or for thecure or prevention of which an inhibition of factor Xa and/or factorVIIa is intended. The invention furthermore relates to processes for thepreparation of compounds of the formula I, their use, in particular asactive ingredients in pharmaceuticals, and pharmaceutical preparationscomprising them.

Normal haemeostasis is the result of a complex balance between theprocesses of clot initiation, formation and clot dissolution. Thecomplex interactions between blood cells, specific plasma proteins andthe vascular surface, maintain the fluidity of blood unless injury andblood loss occurs (EP-A-987274). Many significant disease states arerelated to abnormal haemostasis. For example, local thrombus formationdue to rupture of atheroslerotic plaque is a major cause of acutemyocardial infarction and unstable angina. Treatment of an occlusivecoronary thrombus by either thrombolytic therapy or percutaneousangioplasty may be accompanied by acute thrombolytic reclosure of theaffected vessel.

There continues to be a need for safe and effective therapeuticanticoagulants to limit or prevent thrombus formation. It is mostdesirable to develop agents that inhibit coagulation without directlyinhibiting thrombin but by inhibiting other steps in the coagulationcascade like factor Xa and/or factor VIIa activity. It is now believedthat inhibitors of factor Xa carry a lower bleeding risk than thrombininhibitors (A. E. P. Adang & J. B. M. Rewinkel, Drugs of the Future2000, 25, 369-383).

Low molecular weight, factor Xa-specific blood clotting inhibitors thatare effective but do not cause unwanted side effects have beendescribed, for example, in WO-A-95/29189. However, besides being aneffective factor Xa-specific blood clotting inhibitor, it is desirablethat such inhibitors also have further advantageous properties, forinstance stability in plasma and liver and selectivity versus otherserine proteases whose inhibition is not intended, such as thrombin.There is an ongoing need for further low molecular weight factor Xaspecific blood clotting inhibitors which are effective and have theabove advantages as well.

Specific inhibition of the factor VIIa/tissue factor catalytic complexusing monoclonal antibodies (WO-A-92/06711) or a protein such aschloromethyl ketone inactivated factor VIIa (WO-A-96/12800,WO-A-97/47651) is an extremely effective means of controlling thrombusformation caused by acute arterial injury or the thromboticcomplications related to bacterial septicemia. There is alsoexperimental evidence suggesting that inhibition of factor VIIa/tissuefactor activity inhibits restenosis following balloon angioplasty.Bleeding studies have been conducted in baboons and indicate thatinhibition of the factor VIIa/tissue factor complex has the widestsafety window with respect to therapeutic effectiveness and bleedingrisk of any anticoagulant approach tested including thrombin, plateletand factor Xa inhibition. Certain inhibitors of factor VIIa have alreadybeen described. EP-A-987274, for example discloses compounds containinga tripeptide unit which inhibit factor VIIa. However, the propertyprofile of these compounds is still not ideal, and there is an ongoingneed for further low molecular weight factor VIIa inhibitory bloodclotting inhibitors.

The present invention satisfies the above needs by providing novelcompounds of the formula I which exhibit factor Xa and/or factor VIIainhibitory activity and are favorable agents for inhibiting unwantedblood clotting and thrombus formation.

Thus, the present invention relates to compounds of the formula I,

wherein

-   -   R₀ is        -   1. phenyl, wherein phenyl is unsubstituted or mono-, di- or            trisubstituted independently of one another by R² or        -   2. a mono- or bicyclic 5- to 10-membered heteroaryl            containing one or two nitrogen atoms as ring heteroatoms,            wherein heteroaryl is unsubstituted or mono-, di- or            trisubstituted independently of one another by R²,    -   R² is        -   1. —NO₂,        -   2. halogen,        -   3. —CN,        -   4. —OH,        -   5. —NH₂,        -   6. (C₁-C₈)-alkyloxy-, wherein alkyloxy is unsubstituted or            mono-, di- or trisubstituted independently of one another by            halogen, amino group, hydroxy group or methoxy group, or        -   7. —(C₁-C₈)-alkyl, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by            halogen, amino group, hydroxy group or methoxy group,    -   Q and Q′ are independently of one another identical or different        and are a direct bond, —O—, —S—, —NR¹⁰—, —C(O)NR¹⁰—, —NR¹⁰C(O)—,        —S(O)—, —SO₂—, —NR¹⁰—SO₂—, —SO₂—NR¹⁰-oder-C(O)—;    -   R¹⁰ is hydrogen atom or (C₁-C₄)-alkyl-,    -   X is        -   1. a direct bond,        -   2. (C₁-C₆)-alkylen, wherein alkylen is unsubstituted or            mono-, di- or trisubstituted independently of one another by            halogen, amino group or hydroxy group,        -   3. (C₃-C₆)-cycloalkylen, wherein cycloalkylen is            unsubstituted or mono-, di- or trisubstituted independently            of one another by halogen, amino group or hydroxy group,            provided that at least one of Q, X and Q′ is not a direct            bond,    -   D is an atom out of the group carbon, oxygen, sulfur and        nitrogen, the substructure of formula III    -   is        -   1. a mono- or bicyclic 5- to 10-membered carbocyclic aryl            group, wherein said 5- to 10-membered carbocyclic aryl group            is unsubstituted or mono-, di- or trisubstituted            independently of one another by R¹,        -   2. phenyl, wherein phenyl is unsubstituted or mono-, di- or            trisubstituted independently of one another by R¹,        -   3. a mono- or bicyclic 5-to 10-membered heterocyclic group            (Het), containing one or more heteroatoms as ring            heteroatoms, such as nitrogen, sulfur or oxygen, wherein            said Het group is unsubstituted or mono-, di- or            trisubstituted independently of one another by R¹, or        -   4. pyridyl, wherein pyridyl is unsubstituted or mono-, di-            or trisubstituted independently of one another by R¹,    -   R¹ is        -   1. halogen,        -   2. —NO₂,        -   3. —CN,        -   4. R¹¹R¹²N—, wherein R¹¹R¹² independently of one another are            hydrogen atom, (C₁-C₄)-alkyl- or (C₁-C₆)-acyl-,        -   5. (C₁-C₈)-alkylamino-, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            R¹³,        -   6. —OH,        -   7. —SO₂—NH₂,        -   8. (C₁-C₈)-alkyloxy-, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            R¹³,        -   9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³,        -   10 (C₁-C₈)-alkyl-, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³,        -   11. hydroxycarbonyl-(C₁-C₈)-alkylureido-, wherein alkyl is            unsubstituted or mono-, di- or trisubstituted independently            of one another by R¹³,        -   12. (C₁-C₈)-alkyloxycarbonyl-(C₁-C₈)-alkylureido-, wherein            alkyl is unsubstituted or mono-, di- or trisubstituted            independently of one another by R¹³,        -   13. (C₁-C₈)-alkylsulfonyl-, wherein alkyl is unsubstituted            or mono-, di- or trisubstituted independently of one another            by R¹³, or        -   14. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵ independently of one            another are hydrogen atom or (C₁-C₄)-alkyl-, or    -   two R¹ residues bonded to adjacent ring carbon atoms together        with the carbon atoms to which they are bonded form an aromatic        ring condensed to the ring depicted in formula I, where the ring        formed by the two R¹ residues is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹³, or    -   R¹¹ and R¹² together with the nitrogen atom to which they are        bonded form a saturated or unsaturated 5- to 6-membered        monocyclic heterocyclic ring which in addition to the nitrogen        atom carrying R¹¹ and R¹² can contain one or two identical or        different ring heteroatoms chosen from oxygen, sulfur and        nitrogen, and in which one or two of the ring carbon atoms can        be substituted by oxo to form —C(O)— residue(s),    -   R¹³ is        -   1. halogen,        -   2. —NO₂,        -   3. —CN,        -   4. —OH,        -   5. (C₁-C₈)-alkyl-,        -   6. (C₁-C₈)-alkyloxy-,        -   7. —CF₃ or        -   8. —NH₂,    -   V is a residue of the formulae IIa, IIb, IIc, IId, IIe or IIf,        wherein    -   L is is a direct bond or (C₁-C₃)-alkylene, wherein alkylene is        unsubstituted or mono-, di- or trisubstituted independently of        one another by A,    -   A is        -   1. hydrogen atom,        -   2. —C(O)—OH,        -   3. —C(O)—O—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            —OH, —NH₂ or —(C₁-C₄)-alkoxy,        -   4. —C(O)—NR⁴R⁵,        -   5. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by —OH,            —NH₂ or —(C₁-C₄)-alkoxy,        -   6. —SO₂—NH₂ or        -   7. —SO₂—CH₃,    -   U is —NH₂, (C₁-C₄)-alkyl-,—NH—C(O)—O—(C₁-C₄)-alkyl or        —NH—C(O)—O—(C₁-C₄)-alkyl-aryl,    -   M is hydrogen atom, (C₁-C₃)-alkyl- or —OH,    -   R⁴ and R⁵ are independently of one another identical or        different and are        -   1. hydrogen atom,        -   2. (C₁-C₁₂)-alkyl-, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³ as            defined above,        -   3. (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl-, wherein alkyl and aryl are            unsubstituted or mono-, di- or trisubstituted independently            of one another by R¹³ as defined above,        -   4. (C₆-C₁₄)-aryl-, wherein aryl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³ as            defined above,        -   5. Het-, wherein Het- is unsubstituted or mono-, di- or            trisubstituted independently of one another by R¹³ as            defined above, or        -   6. Het-(C₁-C₄)-alkyl-, wherein alkyl and Het- are            unsubstituted or mono-, di- or trisubstituted independently            of one another by R¹³ as defined above, or    -   R⁴ and R⁵ together with the nitrogen atom to which they are        bonded form a saturated 3- to 8-membered monocyclic heterocyclic        ring which in addition to the nitrogen atom carrying R⁴ and R⁵        can contain one or two identical or different ring heteroatoms        chosen from oxygen, sulfur and nitrogen;        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

Preferred are compounds of the formula I, wherein

-   -   R₀ is phenyl, wherein phenyl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R², or pyridyl,        wherein pyridyl is unsubstituted or mono-, di- or trisubstituted        independently of one another by R²,    -   R²is        -   1. —NO₂,        -   2. halogen,        -   3. —CN,        -   4. —OH,        -   5. —NH₂,        -   6. (C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted or            mono-, di- or trisubstituted independently of one another by            halogen, amino group, hydroxy group or methoxy group, or        -   7. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by            halogen, amino group, hydroxy group or methoxy group,    -   Q, Q′, X, R¹, R¹¹ and R¹² are as defined above,    -   D is an atom out of the group carbon and nitrogen,    -   the substructure of formula III is        -   1. phenyl, wherein phenyl is unsubstituted or mono-, di- or            trisubstituted independently of one another by R¹, or        -   2. pyridyl, wherein pyridyl is unsubstituted or mono-, di-            or trisubstituted independently of one another by R¹,    -   R¹³ is        -   1. halogen,        -   2. —NO₂,        -   3. —CN,        -   4. —OH,        -   5. (C₁-C₄)-alkyl-,        -   6. (C₁-C₄)-alkyloxy-,        -   7. —CF₃ or        -   8. —NH₂,    -   R₁₀ is hydrogen atom or methyl,    -   V is a fragment of the formula IIa, IIb, IIc, IId, IIe or IIf as        defined above, wherein    -   L, U, M, R⁴ and R⁵ are as defined above, and    -   A is        -   1. hydrogen atom,        -   2. —C(O)—OH,        -   3. —C(O)—O—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            —OH, —NH₂ or —(C₁-C₄)-alkoxy,        -   4. —C(O)—NR⁴R⁵or        -   5. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by —OH,            —NH₂ or —(C₁-C₄)-alkoxy.

More preferred are compounds of the formula I, wherein

-   -   R is phenyl, wherein phenyl is mono-, di- or trisubstituted        independently of one another by R², or    -   pyridyl, wherein pyridyl is mono-, di- or trisubstituted        independently of one another by R²,    -   R² is        -   1. —NH₂,        -   2. halogen,        -   3. —CN,        -   4. —OH,        -   5. (C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted or            substituted by an amino group, or        -   6. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or            substituted by an amino group,    -   Q and Q′ are independently of one another identical or different        and are a direct bond, —O—, —C(O)NR¹⁰-, —NR¹⁰C(O)—; —NR¹⁰—SO₂—;        or —SO₂—NR¹⁰—;    -   X is        -   1. a direct bond or        -   2. (C₁-C₄)-alkylen, wherein alkylen is unsubstituted or            mono-, di- or trisubstituted independently of one another by            halogen, amino group or hydroxy group,    -   D is an atom out of the group carbon and nitrogen,    -   the substructure of formula III is        -   phenyl or pyridyl, wherein phenyl and pyridyl are            unsubstituted or mono-, di- or trisubstituted independently            of one another by R¹,    -   R¹ is        -   1. halogen,        -   2. —NO₂,        -   3. —CN,        -   4. —NH₂,        -   5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            R¹³,        -   6. —OH,        -   7. —SO₂—NH₂,        -   8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            R¹³,        -   9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³,        -   10. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³,        -   11. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted            or mono-, di- or trisubstituted independently of one another            by R¹³,        -   12. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵ independently of one            another are hydrogen atom or (C₁-C₄)-alkyl-,        -   13. R¹¹R¹²N—, wherein R¹¹ and R¹² are as defined above, or        -   14. —NR⁴R⁵,    -   R¹³ is        -   1. halogen,        -   2. —NO₂,        -   3. —CN,        -   4. —OH,        -   5. (C₁-C₄)-alkyl-,        -   6. (C₁-C₄)-alkyloxy-,        -   7. —CF₃ or        -   8. —NH₂,    -   R₁₀ is hydrogen atom or methyl,    -   V is a fragment of the formula IIa, IIb, IIc, IId, IIe or IIf as        defined above, wherein    -   L is a direct bond or (C₁-C₃)-alkylen-,    -   A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵        or (C₁-C₄)-alkyl,    -   U is —NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or        —NH—C(O)—O—(CH₂)-phenyl,    -   M is hydrogen atom, (C₁-C₃)-alkyl- or —OH, and    -   R⁴ and R⁵ are independently of one another hydrogen atom or        (C₁-C₄)-alkyl-.

Even more preferred are the compounds of the formula I, wherein

-   -   R₀ is phenyl or pyridyl, wherein phenyl and pyridyl        independently from one another are mono-, di- or trisubstituted        independently of one another by R²,    -   R² is        -   1. halogen,        -   2. —CN,        -   3. (C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted or            substituted by halogen or an amino group, or        -   4. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or            substituted by an amino group or halogen,    -   Q and Q′ are independently of one another identical or different        and are a direct bond, —O—, —C(O)NR¹⁰—, —NR¹⁰C(O)—; —NR¹⁰—SO₂—;        or —SO₂—NR¹⁰—;    -   X is —(C₁-C₃)-alkylen-, wherein alkylen is unsubstituted or        mono-, di- or trisubstituted independently of one another by        halogen, amino group or hydroxy group,    -   D is the atom carbon,    -   the substructure of formula III is        -   phenyl, wherein phenyl is unsubstituted or mono-, di- or            trisubstituted independently of one another by R¹,    -   R¹ is        -   1. halogen,        -   2. —NO₂,        -   3. —CN,        -   4. —NH₂,        -   5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            R¹³,        -   6. —OH,        -   7. —SO₂—NH₂,        -   8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            R¹³,        -   9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³,        -   10. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³,        -   11. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted            or mono-, di- or trisubstituted independently of one another            by R¹³,        -   12. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵independently of one            another are hydrogen atom or (C₁-C₄)-alkyl-,        -   13. R¹¹R¹²N—, wherein R¹¹ and R¹² are as defined above, or        -   14. —NR⁴R⁵, wherein R⁴ and R⁵ are independently of one            another hydrogen atom or methyl    -   R¹³ is        -   1. halogen,        -   2. —CF₃,        -   3. —NH₂,        -   4. —OH,        -   5. (C₁-C₄)-alkyl- or        -   6. (C₁-C₄)-alkyloxy-,    -   R₁₀ is hydrogen atom, and    -   V is a fragment of the formula IIa, IIb, IIc or IId as defined        above, wherein    -   L is a direct bond or (C₁-C₂)-alkylen-,    -   A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵        or (C₁-C₄)-alkyl,    -   U is —NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or        —NH—C(O)—O—(CH₂)-phenyl,    -   M is hydrogen atom or (C₁-C₃)-alkyl-.

Further preferred are compounds of the formula I, wherein

-   -   R₀ is phenyl, wherein phenyl is mono-, di- or trisubstituted        independently of one another by R²,    -   R² is        -   1. halogen,        -   2. (C₁-C₄)-alkyloxy-, wherein alkyloxy is unsubstituted or            substituted by halogen or an amino group, or        -   3. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or            substituted by an amino group or halogen,    -   Q and Q′ are independently of one another identical or different        and are a direct bond, —O—, —C(O)NR¹⁰—, —NR¹⁰C(O)—; —NR¹⁰—SO₂—;        or —SO₂—NR¹⁰—;    -   X is —(C₁-C₃)-alkylen-,    -   D is the atom carbon,    -   the substructure of formula III is        -   phenyl, wherein phenyl is unsubstituted or mono-, di- or            trisubstituted independently of one another by R¹,    -   R¹ is        -   1. halogen,        -   2. —NO₂,        -   3. —CN,        -   4. —NH₂,        -   5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            R¹³,        -   6. —OH,        -   7. —SO₂—NH₂,        -   8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            R¹³,        -   9. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³,        -   10. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted            or mono-, di- or trisubstituted independently of one another            by R¹³,        -   11. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵ independently of one            another are hydrogen atom or (C₁-C₂)-alkyl-,        -   12. R¹¹R¹²N—, wherein R¹¹ and R¹² are as defined above, or        -   13. —NR⁴R⁵,    -   R¹³is        -   1. halogen,        -   2. —CF₃,        -   3. —NH₂,        -   4. —OH,        -   5. (C₁-C₄)-alkyl- or        -   6. (C₁-C₄)-alkyloxy-,    -   R₁₀ is hydrogen atom, and    -   V is a fragment of the formula IIa, IIb, IIc or IId as defined        above, wherein    -   L is a direct bond or (C₁-C₂)-alkylen-,    -   A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵        or —(C₁-C₄)-alkyl,    -   U is —NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or        —NH—C(O)—O—(CH₂)-phenyl,    -   M is hydrogen atom or methyl, and    -   R⁴ and R⁵ are independently of one another hydrogen atom or        methyl.

Particularly preferred are compounds of the formula I, wherein

-   -   R₀ is phenyl, wherein phenyl is disubstituted independently of        one another by R²,    -   R² is 1. halogen,        -   2. (C₁-C₂)-alkyloxy-, wherein alkyloxy is unsubstituted or            substituted by an amino group, or        -   3. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or            substituted by an amino group,    -   Q and Q′ are independently of one another identical or different        and are a direct bond or —O—,    -   X is —CH₂—CH₂—,    -   D is the atom carbon,    -   the substructure of formula III is        -   phenyl, wherein phenyl is unsubstituted or mono-, di- or            trisubstituted independently of one another by R¹,    -   R¹ is        -   1. halogen,        -   2. —OH,        -   3. —NH₂,        -   4. —C(O)—NR¹⁴R¹⁵, wherein R¹⁴R¹⁵ independently of one            another are hydrogen atom or (C₁-C₂)-alkyl-,        -   5. (C₁-C₃)-alkyloxy-, wherein alkyl is unsubstituted or            mono-, di- or trisubstituted independently of one another by            R¹³, or        -   6. (C₁-C₃)-alkyl-, wherein alkyl is unsubstituted or mono-,            di- or trisubstituted independently of one another by R¹³,    -   R¹³ is fluorine or chlorine,    -   R₁₀ is hydrogen atom, and    -   V is a fragment of the formula IIa, IIb, IIc or IId as defined        above, wherein    -   L is a direct bond or (C₁-C₂)-alkylen-,    -   A is hydrogen atom, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵        or —(C₁-C₄)-alkyl,    -   U is —NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or        —NH—C(O)—O—(CH₂)-phenyl,    -   M is hydrogen atom, and    -   R⁴ and R⁵ are independently of one another hydrogen atom or        methyl.

In general, the meaning of any group, residue, heteroatom, number etc.which can occur more than once in the compounds of the formula I, isindependent of the meaning of this group, residue, heteroatom, numberetc. in any other occurrence. All groups, residues, heteroatoms, numbersetc. which can occur more than once in the compounds of the formula Ican be identical or different.

As used herein, the term alkyl is to be understood in the broadest senseto mean hydrocarbon residues which can be linear, i.e. straight-chain,or branched and which can be acyclic or cyclic residues or comprise anycombination of acyclic and cyclic subunits. Further, the term alkyl asused herein expressly includes saturated groups as well as unsaturatedgroups which latter groups contain one or more, for example one, two orthree, double bonds and/or triple bonds, provided that the double bondsare not located within a cyclic alkyl group in such a manner that anaromatic system results. All these statements also apply if an alkylgroup occurs as a substituent on another residue, for example in analkyloxy residue, an alkyloxycarbonyl residue or an arylalkyl residue.Examples of alkyl residues containing 1, 2, 3, 4, 5, 6, 7 or 8carbonatoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl,the n-isomers of all these residues, isopropyl, isobutyl, 1-methylbutyl,isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl,isohexyl, sec-butyl, tert-butyl, tert-pentyl, sec-butyl, tert-butyl ortert-pentyl.

Unsaturated alkyl residues are, for example, alkenyl residues such asvinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl, oralkynyl residues such as ethynyl, 1-propynyl, 2-propynyl (=propargyl) or2-butynyl. Alkyl residues can also be unsaturated when they aresubstituted.

Examples of cyclic alkyl residues are cycloalkyl residues containing 3,4, 5 or 6 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, which can also be substituted and/or unsaturated.Unsaturated cyclic alkyl groups and unsaturated cycloalkyl groups like,for example, cyclopentenyl or cyclohexenyl can be bonded via any carbonatom.

Of course, a cyclic alkyl group has to contain at least three carbonatoms, and an unsaturated alkyl group has to contain at least two carbonatoms. Thus, a group like (C₁-C₈)-alkyl is to be understood ascomprising, among others, saturated acyclic (C₁-C₈)-alkyl,(C₃-C₆)-cycloalkyl, and unsaturated (C₂-C₈)-alkyl like (C₂-C₈)-alkenylor (C₂-C₈)-alkynyl. Similarly, a group like (C₁-C₄)-alkyl is to beunderstood as comprising, among others, saturated acyclic (C₁-C₄)-alkyl,and unsaturated (C₂-C₄)-alkyl like (C₂-C₄)-alkenyl or (C₂-C₄)-alkynyl.

Unless stated otherwise, the term alkyl preferably comprises acyclicsaturated hydro-carbon residues which have from one to six carbon atomsand which can be linear or branched. A particular group of saturatedacyclic alkyl residues is formed by (C₁-C₄)-alkyl residues like methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

Unless stated otherwise, and irrespective of any specific substituentsbonded to alkyl groups which are indicated in the definition of thecompounds of the formula I, alkyl groups can in general be unsubstitutedor substituted by one or more, for example one, two or three, identicalor different substituents. Any kind of substituents present insubstituted alkyl residues can be present in any desired positionprovided that the substitution does not lead to an unstable molecule.Examples of substituted alkyl residues are alkyl residues in which oneor more, for example 1, 2 or 3, hydrogen atoms are replaced with halogenatoms, in particular fluorine atoms.

The term mono- or bicyclic 5- to 10-membered carbocyclic aryl grouprefers to for example phenyl or napthyl.

The term mono- or bicyclic 5- to 10-membered heteroaryl containing oneor two nitrogen atoms as ring heteroatoms refers to (C₅-C₁₀)-aryl inwhich one or more of the 5 to 10 ring carbon atoms are replaced byheteroatoms such as nitrogen, oxygen or sulfur. Examples are pyridyl;such as 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrrolyl; such as 2-pyrrolyland 3-pyrrolyl; furyl; such as 2-furyl and 3-furyl; thienyl; such as2-thienyl and 3-thienyl; imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl,pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl,isoquinolyl or quinoxalinyl.

The term R¹¹ and R¹² together with the nitrogen atom to which they arebonded form a saturated or unsaturated 5- to 6-membered monocyclicheterocyclic ring refers to pyrrol, piperidin, pyrrolidine, morpholine,piperazine, pyridine, pyrimidine, imidazole or thiomorpholine.

The term aryl refers to a monocyclic or polycyclic hydrocarbon residuein which at least one carbocyclic ring is present that has a conjugatedpi electron system. In a (C₆-C₁₄)-aryl residue from 6 to 14 ring carbonatoms are present. Examples of (C₆-C₁₄)-aryl residues are phenyl,naphthyl, biphenylyl, fluorenyl or anthracenyl. Unless stated otherwise,and irrespective of any specific substituents bonded to aryl groupswhich are indicated in the definition of the compounds of the formula I,aryl residues, for example phenyl, naphthyl or fluorenyl, can in generalbe unsubstituted or substituted by one or more, for example one, two orthree, identical or different substituents. Aryl residues can be bondedvia any desired position, and in substituted aryl residues thesubstituents can be located in any desired position.

Unless stated otherwise, and irrespective of any specific substituentsbonded to aryl groups which are indicated in the definition of thecompounds of the formula I, substituents that can be present insubstituted aryl groups are, for example, (C₁-C₈)-alkyl, in particular(C₁-C₄)-alkyl, such as methyl, ethyl or tert-butyl, hydroxy,(C₁-C₈)-alkyloxy, in particular (C₁-C₄)-alkyloxy, such as methoxy,ethoxy or tert-butoxy, methylenedioxy, ethylenedioxy, F, Cl, Br, I,cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxymethyl, formyl,acetyl, amino, mono- or di-(C₁-C₄)-alkylamino,((C₁-C₄)-alkyl)carbonylamino like acetylamino, hydroxycarbonyl,((C₁-C₄)-alkyloxy)carbonyl, carbamoyl, benzyl optionally substituted inthe phenyl group, optionally substituted phenyl, optionally substitutedphenoxy or benzyloxy optionally substituted in the phenyl group. Asubstituted aryl group which is present in a specific position of thecompounds of formula I can independently of other aryl groups besubstituted by substituents selected from any desired subgroup of thesubstituents listed before and/or in the specific definition of thatgroup. For example, a substituted aryl group may be substituted by oneor more identical or different substituents chosen from (C₁-C₄)-alkyl,hydroxy, (C₁-C₄)-alkyloxy, F, Cl, Br, I, cyano, nitro, trifluoromethyl,amino, phenyl, benzyl, phenoxy and benzyloxy. In general, preferably notmore than two nitro groups are present in the compounds of the formulaI.

In monosubstituted phenyl residues the substituent can be located in the2-position, the 3-position or the 4-position, with the 3-position andthe 4-position being preferred. If a phenyl group carries twosubstituents, they can be located in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenylresidues carrying three substituents the substituents can be located in2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position,2,4,6-position, or 3,4,5-position. Naphthyl residues can be 1-naphthyland 2-naphthyl. In substituted naphthyl residues the substituents can belocated in any positions, for example in monosubstituted 1-naphthylresidues in the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position and inmonosubstituted 2-naphthyl residues in the 1-, 3-, 4-, 5-, 6-, 7-, or8-position. Biphenylyl residues can be 2-biphenylyl, 3-biphenylyl and4-biphenylyl. Fluorenyl residues can be 1-, 2-, 3-, 4- or 9-fluorenyl.In monosubstituted fluorenyl residues bonded via the 9-position thesubstituent is preferably present in the 1-, 2-, 3- or 4-position.

The group Het comprises groups containing 5, 6, 7, 8, 9 or 10 ring atomsin the parent monocyclic or bicyclic heterocyclic ring system. Inmonocyclic groups Het the heterocyclic ring preferably is a 5-membered,6-membered or 7-membered ring, particularly preferably a 5-membered or6-membered ring. In bicyclic groups Het preferably two fused rings arepresent one of which is a 5-membered ring or 6-membered heterocyclicring and the other of which is a 5-membered or 6-membered heterocyclicor carbocyclic ring, i.e. a bicyclic ring Het preferably contains 8, 9or 10 ring atoms, particularly preferably 9 or 10 ring atoms.

Het comprises saturated heterocyclic ring systems which do not containany double bonds within the rings, as well as mono-unsaturated andpoly-unsaturated heterocyclic ring systems which contain one or more,for example one, two, three, four or five, double bonds within the ringsprovided that the resulting system is stable. Unsaturated rings may benon-aromatic or aromatic, i.e. double bonds within the rings in thegroup Het may be arranged in such a manner that a conjugated pi electronsystem results. Aromatic rings in a group Het may be 5-membered or6-membered rings, i. e. aromatic groups in a group Het contain 5 to 10ring atoms. Aromatic rings in a group Het thus comprise 5-membered and6-membered monocyclic heterocycles and bicyclic heterocycles composed oftwo 5-membered rings, one 5-membered ring and one 6-membered ring, ortwo 6-membered rings. In bicyclic aromatic groups in a group Het one orboth rings may contain heteroatoms. Aromatic groups Het may also bereferred to by the customary term heteroaryl for which all thedefinitions and explanations above and below relating to Hetcorrespondingly apply.

Unless stated otherwise, in the groups Het and any other heterocyclicgroups preferably 1, 2, 3 or 4 identical or different ring heteroatomschosen from nitrogen, oxygen and sulfur are present. Particularlypreferably in these groups one or two identical or different heteroatomschosen from nitrogen, oxygen and sulfur are present. The ringheteroatoms can be present in any desired number and in any positionwith respect to each other provided that the resulting heterocyclicsystem is known in the art and is stable and suitable as a subgroup in adrug substance. Examples of parent structures of heterocycles from whichthe group Het can be derived are aziridine, oxirane, azetidine, pyrrole,furan, thiophene, dioxole, imidazole, pyrazole, oxazole, isoxazole,thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine,1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine,1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, azepine,1,2-diazepine, 1,3-diazepine, 1,4-diazepine, indole, isoindole,benzofuran, benzothiophene, 1,3-benzodioxole, indazole, benzimidazole,benzoxazole, benzothiazole, quinoline, isoquinoline, chromane,isochromane, cinnoline, quinazoline, quinoxaline, phthalazine,pyridoimidazoles, pyridopyridines, pyridopyrimidines, purine, pteridineetc. as well as ring systems which result from the listed heterocyclesby fusion (or condensation) of a carbocyclic ring, for examplebenzo-fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fusedderivatives of these heterocycles.

The fact that many of the before-listed names of heterocycles are thechemical names of unsaturated or aromatic ring systems does not implythat the groups Het could only be derived from the respectiveunsaturated ring system. The names here only serve to describe the ringsystem with respect to ring size and the number of the heteroatoms andtheir relative positions. As explained above, the group Het can besaturated or partially unsaturated or aromatic, and can thus be derivednot only from the before-listed heterocycles themselves but also fromall their partially or completely hydrogenated analogues and also fromtheir more highly unsaturated analogues if applicable. As examples ofcompletely or partially hydrogenated analogues of the before-listedheterocycles from which the groups Het may be derived the following maybe mentioned: pyrroline, pyrrolidine, tetrahydrofuran,tetrahydrothiophene, dihydropyridine, tetrahydropyridine, piperidine,1,3-dioxolane, 2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol,1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine,perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine (=morpholine),perhydro-1,4-thiazine (=thiomorpholine), perhydroazepine, indoline,isoindoline, 1,2,3,4-tetrahydroquinoline,1,2,3,4-tetrahydroisoquinoline, etc.

The residue Het may be bonded via any ring carbon atom, and in the caseof nitrogen heterocycles via any suitable ring nitrogen atom. Thus, forexample, a pyrrolyl residue can be 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl,a pyrrolidinyl residue can be pyrrolidin-1-yl (=pyrrolidino),pyrrolidin-2-yl or pyrrolidin-3-yl, a pyridinyl residue can bepyridin-2-yl, pyridin-3-yl or pyridin-4-yl, a piperidinyl residue can bepiperidin-1-yl (=piperidino), piperidin-2-yl, piperidin-3-yl orpiperidin-4-yl. Furyl can be 2-furyl or 3-furyl, thienyl can be2-thienyl or 3-thienyl, imidazolyl can be imidazol-1-yl, imidazol-2-yl,imidazol-4-yl or imidazol-5-yl, 1,3-oxazolyl can be 1,3-oxazol-2-yl,1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,3-thiazolyl can be1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl, pyrimidinyl canbe pyrimidin-2-yl, pyrimidin-4-yl (=6-pyrimidinyl) or 5-pyrimidinyl,piperazinyl can be piperazin-1-yl (=piperazin-4-yl =piperazino) orpiperazin-2-yl. Indolyl can be indol-1-yl, indol-2-yl, indol-3-yl,indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl. Similarlybenzimidazolyl, benzoxazolyl and benzothiazol residues can be bonded viathe 2-position and via any of the positions 4, 5, 6, and 7. Quinolinylcan be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl,quinolin-6-yl, quinolin-7-yl or quinolin-8-yl, isoqinolinyl can beisoquinol-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl,isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl. In addition tobeing bonded via any of the positions indicated for quinolinyl andisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl and1,2,3,4-tetrahydroisoquinolinyl can also be bonded via the nitrogenatoms in 1-position and 2-position, respectively.

Unless stated otherwise, and irrespective of any specific substituentsbonded to groups Het or any other heterocyclic groups which areindicated in the definition of the compounds of the formula I, the groupHet can be unsubstituted or substituted on ring carbon atoms with one ormore, for example one, two, three, four or five, identical or differentsubstituents like (C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl,(C₁-C₈)-alkyloxy, in particular (C₁-C₄)-alkyloxy, (C₁-C₄)-alkylthio,halogen, nitro, amino, ((C₁-C₄)-alkyl)carbonylamino like acetylamino,trifluoromethyl, trifluoromethoxy, hydroxy, oxo, hydroxy-(C₁-C₄)-alkylsuch as, for example, hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl,methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, aminosulfonyl,methylsulfonyl, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkyloxycarbonyl, optionally substituted phenyl, optionallysubstituted phenoxy, benzyl optionally substituted in the phenyl group,benzyloxy optionally substituted in the phenyl group, etc. Thesubstituents can be present in any desired position provided that astable molecule results. Of course an oxo group cannot be present in anaromatic ring. Each suitable ring nitrogen atom in a group Het canindependently of each other be unsubstituted, i. e. carry a hydrogenatom, or can be substituted, i.e. carry a substituent like(C₁-C₈)-alkyl, for example (C₁-C₄)-alkyl such as methyl or ethyl,optionally substituted phenyl, phenyl-(C₁-C₄)-alkyl, for example benzyl,optionally substituted in the phenyl group, hydroxy-(C₂-C₄)-alkyl suchas, for example 2-hydroxyethyl, acetyl or another acyl group,methylsulfonyl or another sulfonyl group, aminocarbonyl,(C₁-C₄)-alkyloxycarbonyl, etc. In general, in the compounds of theformula I nitrogen heterocycles can also be present as N-oxides or asquaternary salts. Ring sulfur atoms can be oxidized to the sulfoxide orto the sulfone. Thus, for example a tetrahydrothienyl residue may bepresent as S,S-dioxotetrahydrothienyl residue or a thiomorpholinylresidue like thiomorpholin-4-yl may be present as1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl. A substitutedgroup Het that can be present in a specific position of the compounds offormula I can independently of other groups Het be substituted bysubstituents selected from any desired subgroup of the substituentslisted before and/or in the definition of that group.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine,chlorine or bromine, particularly preferably chlorine or bromine.

Optically active carbon atoms present in the compounds of the formula Ican independently of each other have R configuration or S configuration.The compounds of the formula I can be present in the form of pureenantiomers or pure diastereomers or in the form of mixtures ofenantiomers and/or diastereomers, for example in the form of racemates.The present invention relates to pure enantiomers and mixtures ofenantiomers as well as to pure diastereomers and mixtures ofdiastereomers. The invention comprises mixtures of two or of more thantwo stereoisomers of the formula I, and it comprises all ratios of thestereoisomers in the mixtures. In case the compounds of the formula Ican be present as E isomers or Z isomers (or cis isomers or transisomers) the invention relates both to pure E isomers and pure Z isomersand to E/Z mixtures in all ratios. The invention also comprises alltautomeric forms of the compounds of the formula I.

Diastereomers, including E/Z isomers, can be separated into theindividual isomers, for example, by chromatography. Racemates can beseparated into the two enantiomers by customary methods, for example bychromatography on chiral phases or by resolution, for example bycrystallization of diastereomeric salts obtained with optically activeacids or bases. Stereochemically unifom compounds of the formula I canalso be obtained by employing stereochemically uniform startingmaterials or by using stereoselective reactions.

The choice of incorporating into a compound of the formula I a buildingblock with R configuration or S configuration, or in the case of anamino acid unit present in a compound of the formula I of incorporatinga building block designated as D-amino acid or L-amino acid, can depend,for example, on the desired characteristics of the compound of theformula I. For example, the incorporation of a D-amino acid buildingblock can confer increased stability in vitro or in vivo. Theincorporation of a D-amino acid building block also can achieve adesired increase or decrease in the pharmacological activity of thecompound. In some cases it can be desirable to allow the compound toremain active for only a short period of time. In such cases, theincorporation of an L-amino acid building block in the compound canallow endogenous peptidases in an individual to digest the compound invivo, thereby limiting the individual's exposure to the active compound.A similar effect may also be observed in the compounds of the inventionby changing the configuration in another building block from Sconfiguration to R configuration or vice versa. By taking intoconsideration the medical needs one skilled in the art can determine thedesirable characteristics, for example a favorable stereochemistry, ofthe required compound of the invention.

Physiologically tolerable salts of the compounds of formula I arenontoxic salts that are physiologically acceptable, in particularpharmaceutically utilizable salts. Such salts of compounds of theformula I containing acidic groups, for example a carboxy group COOH,are for example alkali metal salts or alkaline earth metal salts such assodium salts, potassium salts, magnesium salts and calcium salts, andalso salts with physiologically tolerable quarternary ammonium ions suchas tetramethylammonium or tetraethylammonium, and acid addition saltswith ammonia and physiologically tolerable organic amines, such asmethylamine, dimethylamine, trimethylamine, ethylamine, triethylamine,ethanolamine or tris-(2-hydroxyethyl)amine. Basic groups contained inthe compounds of the formula I, for example amino groups or guanidinogroups, form acid addition salts, for example with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid orphosphoric acid, or with organic carboxylic acids and sulfonic acidssuch as formic acid, acetic acid, oxalic acid, citric acid, lactic acid,malic acid, succinic acid, malonic acid, benzoic acid, maleic acid,fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonicacid. Compounds of the formula I which simultaneously contain a basicgroup and an acidic group, for example a guanidino group and a carboxygroup, can also be present as zwitterions (betaines) which are likewiseincluded in the present invention.

Salts of compounds of the formula I can be obtained by customary methodsknown to those skilled in the art, for example by combining a compoundof the formula I with an inorganic or organic acid or base in a solventor dispersant, or from other salts by cation exchange or anion exchange.The present invention also includes all salts of the compounds of theformula I which, because of low physiologically tolerability, are notdirectly suitable for use in pharmaceuticals but are suitable, forexample, as intermediates for carrying out further chemicalmodifications of the compounds of the formula I or as starting materialsfor the preparation of physiologically tolerable salts. The presentinvention furthermore includes all solvates of compounds of the formulaI, for example hydrates or adducts with alcohols.

The invention also includes derivatives and modifications of thecompounds of the formula I, for example prodrugs, protected forms andother physiologically tolerable derivatives, as well as activemetabolites of the compounds of the formula I. The invention relates inparticular to prodrugs and protected forms of the compounds of theformula I which can be converted into compounds of the formula I underphysiological conditions. Suitable prodrugs for the compounds of theformula I, i.e. chemically modified derivatives of the compounds of theformula I having properties which are improved in a desired manner, forexample with respect to solubility, bioavailability or duration ofaction, are known to those skilled in the art. More detailed informationrelating to prodrugs is found in standard literature like, for example,Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985, Fleisher et al.,Advanced Drug Delivery Reviews 19 (1996) 115-130; or H. Bundgaard, Drugsof the Future 16 (1991) 443 which are all incorporated herein byreference. Suitable prodrugs for the compounds of the formula I areespecially acyl prodrugs and carbamate prodrugs of acylatablenitrogen-containing groups such as amino groups and the guanidino groupand also ester prodrugs and amide prodrugs of carboxylic acid groupswhich may be present in compounds of the formula I. In the acyl prodrugsand carbamate prodrugs one or more, for example one or two, hydrogenatoms on nitrogen atoms in such groups are replaced with an acyl groupor a carbamate, preferably a (C₁-C₆)-alkyloxycarbonyl group. Suitableacyl groups and carbamate groups for acyl prodrugs and carbamateprodrugs are, for example, the groups R^(p1)—CO— and R^(p2)O—CO—, inwhich R^(p1) is hydrogen, (C₁-C₂₈)-alkyl, (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C_(1 -C) ₄)-alkyl-, (C₆-C₁₄)-aryl, Het-,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl- or Het-(C₁-C₄)-alkyl- and in which R^(p2)has the meanings indicated for R^(p1) with the exception of hydrogen.

A further embodiement of the present invention are prodrugs of thecompounds of the formula I, preferably (C₁-C₆)-acyl prodrugs and(C₁-C₆)-alkyloxycarbonyl prodrugs.

The present invention also relates to processes of preparation by whichthe compounds of the formula I are obtainable and which comprisecarrying out one or more of the synthesis steps described below. Thecompounds of the formula I can generally be prepared, for example in thecourse of a convergent synthesis, by linkage of two or more fragmentswhich can be derived retrosynthetically from the formula I. In thecourse of the preparation of the compounds of the formula I it cangenerally be advantageous or necessary to introduce functional groupswhich could lead to undesired reactions or side reactions in therespective synthesis step, in the form of precursor groups which arelater converted into the desired functional groups, or to temporarilyblock functional groups by a protective group strategy suited to thesynthesis problem. Such strategies are well known to those skilled inthe art (see, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Wiley, 1991). As examples of precursor groups nitro groupsand cyano groups may be mentioned which can later be converted byreduction, for example by catalytic hydrogenation, into amino groups andaminomethyl groups, respectively. Protective groups can also have themeaning of a solid phase, and cleavage from the solid phase stands forthe removal of the protective group. The use of such techniques is knownto those skilled in the art (Burgess K (Ed.) Solid Phase OrganicSynthesis ,New York: Wiley, 2000). For example, a phenolic hydroxy groupcan be attached to a trityl-polystyrene resin, which serves as aprotecting group, and the molecule is cleaved from this resin bytreatment with TFA at a later stage iof the synthesis.

For example, for the preparation of a compound of the formula I abuilding block of the formula XI,

-   -   in which R₀, Q, Q′, X, are as defined above for the compounds of        the formula I but functional groups can optionally also be        present in the form of precursor groups or can be protected by        protective groups known to those skilled in the art, e.g. an        amino group can be protected with a tert.-butyloxycarbonyl group        or a benzyloxycarbonyl group. R¹′, R¹″, R¹′″, R¹″″, are defined        as hydrogen or as R¹ which has the same meaning as in formula I        but can optionally also be present in the form of precursor        groups or can be protected by protective groups known to those        skilled in the art, e.g. a hydroxy group may be attached to a        polystyrene resin, and Y is a nucleophilically substituable        leaving group or a hydroxyl group, is reacted with a fragment of        the formula III        H—NR₁₀—V   (XII)        in which R₁₀ and V are as defined above for the compounds of the        formula I but functional groups can optionally also be present        in the form of precursor groups or can be protected by        protective groups.

The group COY in the formula XI is preferably the carboxylic acid groupCOOH or an activated carboxylic acid derivative. Y can thus be, forexample, hydroxyl, halogen, in particular chlorine or bromine, alkoxy,in particular methoxy or ethoxy, aryloxy, for example phenoxy orpentafluorophenoxy, phenylthio, methylthio, 2-pyridylthio or a residueof a nitrogen heterocycle bonded via a nitrogen atom, in particular aresidue of an azole, such as, for example, 1-imidazolyl. Y canfurthermore be, for example, ((C₁-C₄)-alkyl)—O—CO—O— or tolylsulfonyloxyand the activated acid derivative can thus be a mixed anhydride.

If Y is hydroxyl, then the carboxylic acid is expediently firstactivated, for example by one of the various methods used for peptidecouplings which are well known to those skilled in the art. Examples ofsuitable activation agents are O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU);(König et al., Proc. 21st Europ. Peptide Symp. 1990 (eds. Giralt,Andreu), Escom, Leiden 1991, p. 143),O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (L. A. Carpino, J. Am. Chem. Soc. 1993,115,4397), or carbodiimides like dicyclohexylcarbo-diimide ordiisopropylcarbodiimide. The activation of the carboxylic acid functionmay also favorably be carried, for example, by conversion of thecarboxylic acid group into the pentafluorophenyl ester usingdicyclohexylcarbodiimide and pentafluorophenol. A number of suitablemethods for the preparation of activated carboxylic acid derivatives arealso indicated with details of source literature in J. March, AdvancedOrganic Chemistry, Fourth Edition, John Wiley & Sons, 1992. Theactivation and the subsequent reaction with the compound of the formulaIII are usually carried in the presence of an inert solvent or diluent,for example DCM, chloroform, THF, diethyl ether, n-heptane, n-hexane,n-pentane, cyclohexane, diisopropyl ether, methyl tert-butyl ether,acetonitrile, DMF, DMSO, dioxane, toluene, benzene, ethyl acetate or amixture of these solvents, if appropriate with addition of a base suchas, for example, potassium tert-butoxide or tributylamine ortriethylamine or diisoprpylethylamine.

The resulting product is a compound of the formula I in which functionalgroups can also be present in the form of precursor groups or can beprotected by protective groups. If still any protective groups orprecursor groups are present they are then removed by known methods (seeGreene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991),or converted in the desired final groups, respectively. E.g., if acarboxylic acid group protected as tert-butyl ester and the freecarboxylic acid is to be prepared as the final compound the protectivegroup can be removed by reaction with trifluoroacetic acid ortert.-butyloxycarbonyl protecting groups can be removed by treatmentwith trifluoroacetic acid. If desired, with the obtained compoundsfurther reactions can then be carried out by standard processes, forexample acylation reactions or esterification reactions, or thecompounds can be converted into physiologically tolerable salts orprodrugs by standard processes known to those skilled in the art.

Other compounds of the formula I can be prepared in a similar fashion asdescribed above by coupling of a fragment of the formula XIII withfragment XII.R₀-Q-X-Q′-W—C(O)—Y   (XIII)in which R₀, Q, Q′, X and Y are as defined above for the compounds ofthe formula I, W is the substructure of formula III, but functionalgroups can optionally also be present in the form of precursor groups orcan be protected by protective groups known to those skilled in the art,e.g. an amino group can be protected with a tert.-butyloxycarbonyl groupor a benzyloxycarbonyl group or a hydroxy group may be attached to apolystyrene resin.

The fragments of the formula XI, XII and XIII are prepared by methodswell known to those skilled in the art (E.g. in J March, AdvancedOrganic Chemistry, ₄ ^(th) Edition, John Wiley & Sons, 1992; R C Larock,Comprehensive Organic Transformations, VCH Publishers, New York 1989).

The compounds of the present invention are serine protease inhibitorswhich inhibit the activity of the blood coagulation enzymes factor Xaand/or factor VIIa. In particular, they are highly active inhibitors offactor Xa. They are specific serine protease inhibitors inasmuch as theydo not substantially inhibit the activity of other proteases whoseinhibition is not desired. The activity of the compounds of the formulaI can be determined, for example, in the assays described below or inother assays known to those skilled in the art. With respect to factorXa inhibition, a preferred embodiment of the invention comprisescompounds which have a Ki≦1 for factor Xa inhibition as determined inthe assay described below, with or without concomitant factor VIIainhibition, and which preferably do not substantially inhibit theactivity of other proteases involved in coagulation and fibrinolysiswhose inhibition is not desired (using the same concentration of theinhibitor). The compounds of the invention inhibit factor Xa catalyticactivity either directly, within the prothrombinase complex or as asoluble subunit, or indirectly, by inhibiting the assembly of factor Xainto the prothrombinase complex.

The present invention also relates to the compounds of the formula Iand/or their physiologically tolerable salts and/or their prodrugs foruse as pharmaceuticals (or medicaments), to the use of the compounds ofthe formula I and/or their physiologically tolerable salts and/or theirprodrugs for the production of pharmaceuticals for inhibition of factorXa and/or factor VIIa or for influencing blood coagulation, inflammatoryresponse or fibrinolysis or for the therapy or prophylaxis of thediseases mentioned above or below, for example for the production ofpharmaceuticals for the therapy and prophylaxis of cardiovasculardisorders, thromboembolic diseases or restenoses. The invention alsorelates to the use of the compounds of the formula I and/or theirphysiologically tolerable salts and/or their prodrugs for the inhibitionof factor Xa and/or factor VIIa or for influencing blood coagulation orfibrinolysis or for the therapy or prophylaxis of the diseases mentionedabove or below, for example for use in the therapy and prophylaxis ofcardiovascular disorders, thromboembolic diseases or restenoses, and tomethods of treatment aiming at such purposes including methods for saidtherapies and prophylaxis. The present invention also relates topharmaceutical preparations (or pharmaceutical compositions) whichcontain an effective amount of at least one compound of the formula Iand/or its physiologically tolerable salts and/or its prodrugs inaddition to a customary pharmaceutically acceptable carrier, i. e. oneor more pharmaceutically acceptable carrier substances or excipientsand/or auxiliary substances or additives.

Preferred are the treatment of disease states such as abnormal thrombusformation, acute myocardial infarction, unstable angina,thromboembolism, acute vessel closure associated with thrombolytictherapy or percutaneous transluminal coronary angioplasty, transientischemic attacks, stroke, pathologic thrombus formation occuring in theveins of the lower extremities following abdominal, knee and hipsurgery, a risk of pulmonary thromboembolism, or disseminated systemicintravascular coagulatopathy ocurring in vascular systems during septicshock, certain viral infections or cancer.

The compounds of the formula I and their physiologically tolerable saltsand their prodrugs can be administered to animals, preferably tomammals, and in particular to humans as pharmaceuticals for therapy orprophylaxis. They can be administered on their own, or in mixtures withone another or in the form of pharmaceutical preparations which permitenteral or parenteral administration.

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, lacquered tablets, coated tablets, granules, hard andsoft gelatin capsules, solutions, syrups, emulsions, suspensions oraerosol mixtures. Administration, however, can also be carried outrectally, for example in the form of suppositories, or parenterally, forexample intravenously, intramuscularly or subcutaneously, in the form ofinjection solutions or infusion solutions, microcapsules, implants orrods, or percutaneously or topically, for example in the form ofointments, solutions or tinctures, or in other ways, for example in theform of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention are preparedin a manner known per se and familiar to one skilled in the art,pharmaceutically acceptable inert inorganic and/or organic carriersbeing used in addition to the compound(s) of the formula I and/or its(their) physiologically tolerable salts and/or its (their) prodrugs. Forthe production of pills, tablets, coated tablets and hard gelatincapsules it is possible to use, for example, lactose, corn starch orderivatives thereof, talc, stearic acid or its salts, etc. Carriers forsoft gelatin capsules and suppositories are, for example, fats, waxes,semisolid and liquid polyols, natural or hardened oils, etc. Suitablecarriers for the production of solutions, for example injectionsolutions, or of emulsions or syrups are, for example, water, saline,alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetableoils, etc. Suitable carriers for microcapsules, implants or rods are,for example, copolymers of glycolic acid and lactic acid. Thepharmaceutical preparations normally contain about 0.5% to 90% by weightof the compounds of the formula I and/or their physiologically tolerablesalts and/or their prodrugs. The amount of the active ingredient of theformula I and/or its physiologically tolerable salts and/or its prodrugsin the pharmaceutical preparations normally is from about 0.5 mg toabout 1000 mg, preferably from about 1 mg to about 500 mg.

In addition to the active ingredients of the formula I and/or theirphysiologically acceptable salts and/or prodrugs and to carriersubstances, the pharmaceutical preparations can contain additives suchas, for example, fillers, disintegrants, binders, lubricants, wettingagents, stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants. They canalso contain two or more compounds of the formula I and/or theirphysiologically tolerable salts and/or their prodrugs. In case apharmaceutical preparation contains two or more compounds of the formulaI the selection of the individual compounds can aim at a specificoverall pharmacological profile of the pharmaceutical preparation. Forexample, a highly potent compound with a shorter duration of action maybe combined with a long-acting compound of lower potency. Theflexibility permitted with respect to the choice of substituents in thecompounds of the formula I allows a great deal of control over thebiological and physico-chemical properties of the compounds and thusallows the selection of such desired compounds. Furthermore, in additionto at least one compound of the formula I and/or its physiologicallytolerable salts and/or its prodrugs, the pharmaceutical preparations canalso contain one or more other therapeutically or prophylacticallyactive ingredients.

As inhibitors of factor Xa and/or factor VIIa the compounds of theformula I and their physiologically tolerable salts and their prodrugsare generally suitable for the therapy and prophylaxis of conditions inwhich the activity of factor Xa and/or factor VIIa plays a role or hasan undesired extent, or which can favorably be influenced by inhibitingfactor Xa and/or factor VIIa or decreasing their activities, or for theprevention, alleviation or cure of which an inhibition of factor Xaand/or factor VIIa or a decrease in their activity is desired by thephysician. As inhibition of factor Xa and/or factor VIIa influencesblood coagulation and fibrinolysis, the compounds of the formula I andtheir physiologically tolerable salts and their prodrugs are generallysuitable for reducing blood clotting, or for the therapy and prophylaxisof conditions in which the activity of the blood coagulation systemplays a role or has an undesired extent, or which can favorably beinfluenced by reducing blood clotting, or for the prevention,alleviation or cure of which a decreased activity of the bloodcoagulation system is desired by the physician. A specific subject ofthe present invention thus are the reduction or inhibition of unwantedblood clotting, in particular in an individual, by administering aneffective amount of a compound I or a physiologically tolerable salt ora prodrug thereof, as well as pharmaceutical preparations therefor.

Conditions in which a compound of the formula I can be favorably usedinclude, for example, cardiovascular disorders, thromboembolic diseasesor complications associated, for example, with infection or surgery. Thecompounds of the present invention can also be used to reduce aninflammatory response. Examples of specific disorders for the treatmentor prophylaxis of which the compounds of the formula I can be used arecoronary heart disease, myocardial infarction, angina pectoris, vascularrestenosis, for example restenosis following angioplasty like PTCA,adult respiratory disstress syndrome, multi-organ failure, stroke anddisseminated intravascular clotting disorder. Examples of relatedcomplications associated with surgery are thromboses like deep vein andproximal vein thrombosis which can occur following surgery. In view oftheir pharmacological activity the compounds of the invention canreplace or supplement other anticoagulant agents such as heparin. Theuse of a compound of the invention can result, for example, in a costsaving as compared to other anticoagulants.

When using the compounds of the formula I the dose can vary within widelimits and, as is customary and is known to the physician, is to besuited to the individual conditions in each individual case. It depends,for example, on the specific compound employed, on the nature andseverity of the disease to be treated, on the mode and the schedule ofadministration, or on whether an acute or chronic condition is treatedor whether prophylaxis is carried out. An appropriate dosage can beestablished using clinical approaches well known in the medical art. Ingeneral, the daily dose for achieving the desired results in an adultweighing about 75 kg is from 0.01 mg/kg to 100 mg/kg, preferably from0.1 mg/kg to 50 mg/kg, in particular from 0.1 mg/kg to 10 mg/kg, (ineach case in mg per kg of body weight). The daily dose can be divided,in particular in the case of the administration of relatively largeamounts, into several, for example 2, 3 or 4, part administrations. Asusual, depending on individual behavior it may be necessary to deviateupwards or downwards from the daily dose indicated.

A compound of the formula I can also advantageously be used as ananticoagulant outside an individual. For example, an effective amount ofa compound of the invention can be contacted with a freshly drawn bloodsample to prevent coagulation of the blood sample. Further, a compoundof the formula I and its salts can be used for diagnostic purposes, forexample in in vitro diagnoses, and as an auxiliary in biochemicalinvestigations. For example, a compound of the formula I can be used inan assay to identify the presence of factor Xa and/or factor VIIa or toisolate factor Xa and/or factor VIIa in a substantially purified form. Acompound of the invention can be labeled with, for example, aradioisotope, and the labeled compound bound to factor Xa and/or factorVIIa is then detected using a routine method useful for detecting theparticular label. Thus, a compound of the formula I or a salt thereofcan be used as a probe to detect the location or amount of factor Xaand/or factor VIIa activity in vivo, in vitro or ex vivo.

Furthermore, the compounds of the formula I can be used as synthesisintermediates for the preparation of other compounds, in particular ofother pharmaceutical active ingredients, which are obtainable from thecompounds of the formula I, for example by introduction of substituentsor modification of functional groups.

It is understood that changes that do not substantially affect theactivity of the various embodiments of this invention are includedwithin the invention disclosed herein. Thus, the following examples areintended to illustrate but not limit the present invention.

EXAMPLES

Abbreviations used: tert-Butyl tBu Dichloromethane DCM Diethylazodicarboxylate DEAD Diisopropyl azodicarboxylate DIADN,N′-Diisopropylcarbodiimide DIC N,N-Diisopropyl-N-ethylamine DIEAN,N-Dimethylformamide DMF Dimethylsulfoxide DMSOO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- HATUtetramethyluronium-hexafluorophosphate 1-Hydroxy-7-azabenzotriazole HOAtN-Ethylmorpholine NEM Methanol MeOH Tetrahydrofuran THF Trifluoroaceticacid TFA

When in the final step of the synthesis of a compound an acid such astrifluoroacetic acid or acetic acid was used, for example whentrifluoroacetic acid was employed to remove a tert-butyl group or when acompound was purified by chromatography using an eluent which containedsuch an acid, in some cases, depending on the work-up procedure, forexample the details of a freeze-drying process, the compound wasobtained partially or completely in the form of a salt of the acid used,for example in the form of the acetic acid salt or trifluoroacetic acidsalt or hydrochloric acid salt.

Example 1(S)-(1-Carbamimidoyl-piperidin-4-yl)-{3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-hydroxy-benzoylamino}-aceticacid methyl ester

(a) 3,5-Dihydroxy-benzoic acid allyl ester

To 1.5 g of 3,5-dihydroxybenzoic acid in screw-capped vial was added 10g of allyl alcohol and the vial was closed and cooled to −20° C. To thecold contents of the reaction vial was added 5 mL of trimethylsilylchloride via syringe through a septum. The reaction vial was allowed towarm to room temperature and agitated for 16 hours. The vial was openedcarefully and its contents transferred to a round-bottomed flask. Thesolvent was removed under reduced pressure and the residual solid wasdried under reduced pressure over potassium hydroxide pellets for 12 h.The semisolid product was used in the subsequent synthetic steps withoutfurther purification. The product was analyzed by HPLC and had aretention time of 3.65 on 5 cm C₁₈ reversed phase column with flow rateof 2.5 mL/min of pure acetonitrile (for solvent A) and 0.1% aqueoustrifluroacetic acid (for solvent B). The product was characterized by ¹HNMR (DMSO-d₆, 350 MHz): δ=6.87 (s, 2H, aromatic); 6.44 (s, 1H,aromatic); 5.85-5.96 (m, 1H); 5.16-5.33 (m, 2H); 4.65-4.67(dd, 2H).

(b) 300 mg of (2′-chloro)-Chlorotrityl-polystyrene resin (0.39 mmols;loading 1.3 mmol/g Cl) was treated with 4 mL of dichloroethane and theresin was left to swell at room temperature for 30 minutes. The solventwas removed by filtration and the resin was treated with a solution of227 mg of 3,5-dihydroxy-benzoic acid allyl ester and 0.4 mL of DIEA in 5mL anhydrous dichloromethane. The resin suspension was agitated for 3 to4 h at 60° C. The resin was washed with DMF (3 times), DCM (5 times) andDMF (5 times) and used in next step.

(c) The resin from step (b) was washed with anhydrous THF (3 times) andsuspended in 4 mL of anhydrous THF containing 511 mg oftriphenylphosphine and 745 mg of 2,4-dichlorophenethyl alcohol. Thesuspension was cooled to −15° C. and 0.384 mL of DIAD was added. Theresin suspension was agitated at room temperature for 12 h. The solventwas removed by filtration and the resin was washed with THF (9 times),DMF (5 times), DCM (5 times). The resin was used in the next step.

(d) The resin from step (c) was suspended in DCM and 365 mg of1,3-dimethylbarbituric acid was added in the presence of 45 mg of Pd(0)(PPh₃)₄ under argon. The resin suspension was agitated for one hourat room temperature. The solvent was removed by filtration and the resinwas washed with DCM and dried.

(e) Dried resin from step (d) was washed with DMF and suspended in 3 mLDMF containing 265 mg of HOAt and 0.302 mL of DIC. The resin wasagitated for 5 minutes and 613 mg of(S)-amino-[1-(tert-butoxycarbonylamino-imino-methyl)-piperidin-4-yl]-aceticacid methyl ester was added. The resin suspension was agitated for 12 h.The resin was washed with DMF and DCM and dried under reduced pressurefor 6-8 h.

(f) The dried resin from step (e) was suspended in DCM containing 50%TFA and agitated at room temperature for 45 minutes. The resinsuspension was filtered, washed with DCM: TFA (1:1) and the washingscombined with the cleavage filtrate. The cleavage solution was driedunder reduced pressure. The solid product was lyophilized from 30%aqueous acetonitrile and crude product purified by HPLC on reverse phaseC₁₈ column. Fractions containing the desired product were pooled andlyophilized to give(S)-(1-Carbamimidoyl-piperidin-4-yl)-{3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-hydroxy-benzoylamino}-aceticacid methyl ester as a white solid. The product was identified by LC/MSto give m/e=523 (M+H)⁺.

Example 24-Bromo-N-(1-carbamimidoyl-piperidin-4-ylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-hydroxy-benzamide

(a) 4-Bromo-3,5-dihydroxy-benzoic acid allyl ester

This compound was prepared analogously to 3,5-Dihydroxy-benzoic acidallyl ester [Example 1 (a)], however 4-bromo-3,5-dihydroxybenzoic acidwas used instead of 3,5-dihydroxybenzoic acid. ¹H NMR (DMSO-d₆, 350MHz): δ=7.04 (s, 2H, aromatic); 5.97-6.06 (m, 1H); 5.25-5.40 (m, 2H);4.73-4.75(dd, 2H).

(b) The title compound was synthesized analogously to Example 1, steps(b)-(f) with the following differences:

In step (b) 4-Bromo-3,5-dihydroxy-benzoic acid allyl ester was usedinstead of 3,5-dihydroxy-benzoic acid allyl ester;

In step (e) [(4-aminomethyl-piperidin-1-yl)-imino-methyl]-carbamic acidtert-butyl ester was used instead of(S)-amino-[1-(tert-butoxycarbonylamino-imino-methyl)-piperidin-4-yl]-aceticacid methyl ester. The final product was purified by HPLC andcharacterized by LC/MS to give m/e=543.3 (M+H)⁺.

Example 3N-(1-Carbamimidoyl-piperidin-4-ylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-hydroxy-4-methyl-benzamide

(a) 3,5-dihydroxy-4-methylbenzoic acid allyl ester

This compound was prepared analogously to 3,5-Dihydroxy-benzoic acidallyl ester [Example 1 (a)], however 3,5-dihydroxy-4-methylbenzoic acidwas used instead of 3,5-dihydroxybenzoic acid.

(b) The title compound was synthesized analogously to Example 2, withthe following difference:

3,5-dihydroxy-4-methyl-benzoic acid allyl ester was used instead of4-Bromo-3,5-dihydroxy-benzoic acid allyl ester. The final product waspurified by HPLC and characterized by LC/MS to give m/e=478.8 (M+H)⁺.

Analogously to the above examples the following example compounds wereprepared by similar procedures and characterized by LC/MS: ExampleStructure MWt (M + H)⁺ 4

464.13 465.3 5

536.15 537.3 6

564.10 565.3 7

513.22 514.3 8

523.10 524 9

411.23 412 10

475.11 476

Example 11N-(1-Carbamimidoyl-piperidin-4-ylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

(a) 3-Hydroxy-4-methoxy-benzoic acid methyl ester

10 mL of thionyl chloride was added to 250 mL of methanol at 0° C. Thesolution was stirred for 10 minutes and 25 g of3-hydroxy-4-methoxybenzoic acid were added. The reaction was stirred for16 h at room temperature then heated to 50° C. for 3 h. The solventswere removed under reduced pressure. The residue was used directly inthe next step.

(b) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid methylester

20 g of triphenylphosphine and 10 g of 3-Hydroxy-4-methoxy-benzoic acidmethyl ester were dissolved in 200 mL of anhydrous THF. The solution wascooled to 0° C. to 10° C. and a solution of 11.4 mL DEAD in 30 mLanhydrous THF was added dropwise over 20 min. The reaction was warmed toroom temperature and stirred for 45 min. A solution of 11.3 mL2-(2,4-Dichlorophenyl)-ethanol in 10 mL anhydrous THF was added withcooling. The reaction was stirred at room temperature for 16 h, then thesolvents were removed under reduced pressure. The residue was treatedwith n-heptane:ethyl acetate/4:1. The filtrate was dried under reducedpressure. The product was purified by silica gel chromatography, elutingwith n-heptane:ethyl acetate/4:1, then n-heptane:ethyl acetate/3:1.Yield 17 g.

(c) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid

17 g of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid methylester was dissolved in 200 mL of methanol:water/3:1. 4.1 g of lithiumhydroxide monohydrate was added to the solution, and the reaction wasstirred at room temperature for 16 h then at 90° C. for 2 h. Thesolution was cooled to room temperature, then acidified withhalf-concentrated hydrochloric acid. The solvents were removed underreduced pressure and the residue was washed twice with warm water toremove salts.

(d) A solution of 100 mg3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid in 2 ml DMF wasactivated by the addition of 53 mg carbonyldiimidazole. After stirringfor 2 h at RT 90 mg of 4-Aminomethyl-piperidine-1-carboxamidinehydrochloride and 2 ml DMSO were added and the mixture was stirredovernight. Subsequent dilution with 3 ml water and filtration through achem elut® cartridge, eluting with ethyl acetate yielded afterconcentration under reduced pressure a white solid. Purification bypreparative HPLC (C₁₈ reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) and lyophilisation afforded 30 mg (20%) of thetitle compound as a white powder.

MS (ESI +) m/e 479.3 (M+H) chloro pattern.

Example 123-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-[1-(10-imino-ethyl)-piperidin-4-ylmethyl]-4-methyl-benzamide;compound with trifluoro-acetic acid

50 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid and58.9 mg of C-[1-(1-imino-ethyl)-piperidin-4-yl]-methylaminedi-trifluoroacetic acid salt were dissolved in 5 ml of DMF. Aftercooling to 0° C. 64.3 mg of HATU and 70.8 mg of NEM were added. Themixture was stirred at 0° C. for 2 hours and at room temperature for 3hours. The solvent was removed under reduced pressure and the residuewas purified by preparative HPLC (C18 reverse phase column) (gradientacetonitrile water (containing 0.1% trifluoro-acetic acid) 90:10 to0:100). The fractions containing the product were evaporated andlyophilized. Yield: 48 mg (54%), MS: 462.2/464.3 (M+H)⁺.

Example 13N-(1-Carbamimidoyl-piperidin-4-ylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzamide;compound with trifluoro-acetic acid

50 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid and35.2 mg of 4-aminomethyl-piperidine-1-carboxamidine dihydrochloride weredissolved in 5 ml of DMF. After cooling to 0° C. 64.3 mg of HATU and70.8 mg of NEM were added. The mixture was stirred at 0° C. for 2 hoursand at room temperature for 3 hours. The solvent was removed underreduced pressure and the residue was purified by preparative HPLC (C₁₈reverse phase column) (gradient acetonitrile water (containing 0.1%trifluoro-acetic acid) 90:10 to 0:100). The fractions containing theproduct were evaporated and lyophilized.

Yield: 45 mg (51%), MS: 463.3/465.3 (M+H)⁺.

Example 14{Amino-[4-({3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzoylamino}-methyl)-piperidin-1-yl]-methylene}-carbamicacid benzyl ester

97 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid and124.3 mg of [Amino-(4-aminomethyl-piperidin-1-yl)-methylene]-carbamicacid benzyl ester trifluoroacetic acid salt were dissolved in 5 ml ofDMF. After cooling to 0° C. 136 mg of HATU and 106 mg of NEM were added.The mixture was stirred at 0° C. for 2 hours and at room temperature for3 hours. The solvent was removed under reduced pressure and the residuewas purified by preparative HPLC (C₁₈ reverse phase column) (gradientacetonitrile water (containing 0.1% trifluoro-acetic acid) 90:10 to0:100). The fractions containing the product were evaporated andlyophilized.

Yield: 146 mg (79.5%), MS: 597.3/599.3 (M+H)⁺.

Pharmacological Testing

The ability of the compounds of the formula I to inhibit factor Xa orfactor VIIa or other enzymes like thrombin, plasmin, or trypsin can beassessed by determining the concentration of the compound of the formulaI that inhibits enzyme activity by 50%, i.e. the IC₅₀ value, which isrelated to the inhibition constant Ki. Purified enzymes are used inchromogenic assays. The concentration of inhibitor that causes a 50%decrease in the rate of substrate hydrolysis is determined by linearregression after plotting the relative rates of hydrolysis (compared tothe uninhibited control) versus the log of the concentration of thecompound of formula I. For calculating the inhibition constant Ki, theIC₅₀ value is corrected for competition with substrate using the formulaKi=IC ₅₀/{1+(substrate concentration/Km)}wherein Km is the Michaelis-Menten constant (Chen and Prusoff, Biochem.Pharmacol. 22 (1973), 3099-3108; I. H. Segal, Enzyme Kinetics, 1975,John Wiley & Sons, New York, 100-125; which are incorporated herein byreference).a) Factor Xa Assay

In the assay for determining the inhibition of factor Xa activityTBS-PEG buffer (50 mM Tris-HCl, pH 7.8, 200 mM NaCl, 0.05% (w/v)PEG-8000, 0.02% (w/v) NaN₃) was used. The IC₅₀ was determined bycombining in appropriate wells of a Costar half-area microtiter plate 25μl human factor Xa (Enzyme Research Laboratories, Inc.; South Bend,Ind.) in TBS-PEG; 40 μl 10% (v/v) DMSO in TBS-PEG (uninhibited control)or various concentrations of the compound to be tested diluted in 10%(v/v) DMSO in TBS-PEG; and substrate S-2765(N(α)-benzyloxycarbonyl-D-Arg-Gly-L-Arg-p-nitroanilide; Kabi Pharmacia,Inc.; Franklin, Ohio) in TBS-PEG.

The assay was performed by pre-incubating the compound of formula I plusenzyme for 10 min. Then the assay was initiated by adding substrate toobtain a final volume of 100 μl. The initial velocity of chromogenicsubstrate hydrolysis was measured by the change in absorbance at 405 nmusing a Bio-tek Instruments kinetic plate reader (Ceres UV900HDi) at 25°C. during the linear portion of the time course (usually 1.5 min afteraddition of substrate). The enzyme concentration was 0.5 nM andsubstrate concentration was 140 μM.

b) Factor VIIa Assay

The inhibitory activity towards factor VIIa/tissue factor activity wasdetermined using a chromogenic assay essentially as described previously(J. A. Ostrem et al., Biochemistry 37 (1998) 1053-1059 which isincorporated herein by reference). Kinetic assays were conducted at 25°C. in half-area microtiter plates (Costar Corp., Cambridge, Mass.) usinga kinetic plate reader (Molecular Devices Spectramax 250). A typicalassay consisted of 25 μl human factor VIIa and TF (5 nM and 10 nM,respective final concentration) combined with 40 μl of inhibitordilutions in 10% DMSO/TBS-PEG buffer (50 mM Tris, 15 mM NaCl, 5 mMCaCl₂, 0.05% PEG 8000, pH 8.15). Following a 15 minute preincubationperiod, the assay was initiated by the addition of 35 μl of thechromogenic substrate S-2288 (D-IIe-Pro-Arg-p-nitroanilide, PharmaciaHepar Inc., 500 μM final concentration).

The following test results (inhibition constants Ki (FXa) for inhibitionof factor Xa) were obtained:

-   -   Example 1: Ki(FXa) 2.116 micromolar    -   Example 2: Ki(FXa) 0.0137 micromolar    -   Example 3: Ki(FXa) 0.0585 micromolar    -   Example 4: Ki(FXa) 0.4635 micromolar    -   Example 6: Ki(FXa) 2.280 micromolar    -   Example 11: Ki(FXa) 0.189 micromolar    -   Example 12: Ki(FXa) 0.14 micromolar    -   Example 13: Ki(FXa) 0.173 micromolar    -   Example 14: Ki(FXa) 5.077 micromolar (Prodrug)

1-11. (canceled)
 12. A compound of formula I,

wherein R₀ is phenyl, wherein the phenyl is mono-, di- or trisubstitutedindependently of one another by R², or a mono- or bicyclic 5- to10-membered heteroaryl containing one or two nitrogen atoms as ringheteroatoms, wherein the heteroaryl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R²; R is —NO₂, halogen,—CN, —OH, —NH₂, —(C₁-C₈)-alkyloxy, wherein the alkyloxy is unsubstitutedor mono-, di- or trisubstituted independently of one another by halogen,amino, hydroxy or methoxy, or —(C₁-C₈)-alkyl, wherein the alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by halogen, amino, hydroxy or methoxy; one of Q and Q′ is directbond and the other is —O—; R¹⁰ is hydrogen or (C₁-C₄)-alkyl; X is(C₁-C₆)-alkylene, wherein the alkylene is unsubstituted or mono-, di- ortrisubstituted independently of one another by halogen, amino orhydroxy; the substructure of formula III

is a mono- or bicyclic 5- to 10-membered carbocyclic aryl group, whereinthe 5- to 10-membered carbocyclic aryl group is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹, phenyl,wherein the phenyl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹, Het, wherein the Het is a mono- orbicyclic 5-to 10-membered heterocyclic group, containing one or moreheteroatoms chosen from nitrogen, sulfur and oxygen, and wherein the Hetis unsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹, or pyridyl, wherein the pyridyl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹; D iscarbon, oxygen, sulfur or nitrogen, R¹ is halogen, —NO₂, —CN, —OH,—SO₂—NH₂, R¹¹R¹²N—, (C₁-C₈)-alkylamino-, (C₁-C₈)-alkyloxy,(C₁-C₈)-alkyl, hydroxycarbonyl-(C₁-C₈)-alkylureido-,(C₁-C₈)-alkyloxycarbonyl-(C₁-C₈)-alkylureido- or (C₁-C₈)-alkylsulfonyl-,wherein the alkyl of each group is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³, (C₆-C₁₄)-aryl,wherein the aryl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³, or —C(O)—NR¹⁴R¹⁵, or two R¹residues bonded to adjacent ring carbon atoms together with the carbonatoms to which they are bonded form an aromatic ring condensed to thering depicted in formula I, where the ring formed by the two R¹ residuesis unsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³; R¹¹ and R¹² are each, independently, hydrogen,(C₁-C₄)-alkyl or (C₁-C₆)-acyl, or R¹¹ and R¹² together with the nitrogenatom to which they are bonded form a saturated or unsaturated 5- to6-membered monocyclic heterocyclic ring, wherein the 5- to 6-memberedmonocyclic heterocyclic ring can additionally contain one or twoidentical or different ring heteroatoms chosen from oxygen, sulfur andnitrogen, and wherein one or two of the ring carbon atoms are optionallysubstituted by oxo to form —C(O)—residue(s); R¹⁴ and R¹⁵ are each,independently, hydrogen or (C₁-C₄)-alkyl; R¹³ is halogen, —NO₂, —CN,—OH, —(C₁-C₈)-alkyl, —(C₁-C₈)-alkyloxy, —CF₃ or —NH₂, V is a residue offormulae IIa, IIb, IIc, IId, IIe or IIf,

L is direct bond or (C₁-C₃)-alkylene, wherein the alkylene isunsubstituted or mono-, di- or trisubstituted independently of oneanother by A; A is hydrogen, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, whereinthe alkyl is unsubstituted or mono-, di- or trisubstituted independentlyof one another by —OH, —NH₂ or —(C₁-C₄)-alkoxy, —C(O)—NR⁴R⁵,—(C₁-C₄)-alkyl, wherein the alkyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by —OH, —NH₂ or—(C₁-C₄)-alkoxy, —SO₂—NH₂, or —SO₂—CH₃; U is —NH₂, (C₁-C₄)-alkyl,—NH—C(O)—O—(C₁-C₄)-alkyl or —NH—C(O)—O—(C₁-C₄)-alkyl-aryl; M ishydrogen, (C₁-C₃)-alkyl or —OH; and R⁴ and R⁵ are each, independently,hydrogen, (C₁-C₁₂)-alkyl, wherein the alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹³,(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl, wherein the alkyl and aryl are each,independently, unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³, (C₆-C₁₄)-aryl, wherein the aryl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³, Het, wherein the Het is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹³, orHet-(C₁-C₄)-alkyl-, wherein the alkyl and Het are each, independently,unsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³, or R⁴ and R⁵ together with the nitrogen atom to whichthey are bonded form a saturated 3- to 8-membered monocyclicheterocyclic ring, wherein the 3- to 8-membered monocyclic heterocyclicring can additionally contain one or two identical or different ringheteroatoms chosen from oxygen, sulfur and nitrogen; or a stereoisomericform or a mixture of stereoisomeric forms thereof in any ratio, or aphysiologically tolerable salt, or a prodrug thereof.
 13. The compoundaccording to claim 12, wherein R₀ is phenyl, wherein the phenyl ismono-, di- or trisubstituted independently of one another by R², orpyridyl, wherein the pyridyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R², R² is —NO₂, halogen,—CN, —OH, —NH², —(C₁-C₄)-alkyloxy, wherein the alkyloxy is unsubstitutedor mono-, di- or trisubstituted independently of one another by halogen,amino, hydroxy or methoxy, or —(C₁-C₄)-alkyl, wherein the alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by halogen, amino, hydroxy or methoxy; R¹⁰ is hydrogen ormethyl; the substructure of formula III is phenyl or pyridyl, whereinthe phenyl and pyridyl are each independently, unsubstituted or mono-,di- or trisubstituted independently of one another by R¹; D is carbon ornitrogen; R¹³ is halogen, —NO₂, —CN, —OH, —(C₁-C₄)-alkyl,—(C₁-C₄)-alkyloxy, —CF₃ or —NH₂; and A is hydrogen, —C(O)—OH,—C(O)—O—(C₁-C₄)-alkyl, wherein the alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by —OH, —NH₂ or—(C₁-C₄)-alkoxy, —C(O)—NR⁴R⁵, or (C₁-C₄)-alkyl-, wherein the alkyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by —OH, —NH₂ or —(C₁-C₄)-alkoxy.
 14. The compound according toclaim 12, wherein R₀ is phenyl or pyridyl, wherein the phenyl andpyridyl are each, independently, mono-, di- or trisubstitutedindependently of one another by R²; R² is —NH₂, halogen, —CN, —OH,—(C₁-C₄)-alkyloxy, wherein the alkyloxy is unsubstituted or substitutedby amino, or —(C₁-C₄)-alkyl, wherein the alkyl is unsubstituted orsubstituted by amino; R₁₀ is hydrogen or methyl; X is (C₁-C₄)-alkylene,wherein the alkylene is unsubstituted or mono-, di- or trisubstitutedindependently of one another by halogen, amino or hydroxy; thesubstructure of formula III is phenyl or pyridyl, wherein the phenyl andpyridyl are each, independently, unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹; D is carbon ornitrogen, R¹ is halogen, —NO₂, —CN, —OH, —SO₂—NH₂, (C₁-C₄)-alkylamino-,(C₁-C₄)-alkyloxy, (C₁-C₄)-alkyl, or (C₁-C₄)-alkylsulfonyl-, wherein thealkyl of each group is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³, or (C₆-C₁₄)-aryl, wherein the arylis unsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹³, —C(O)—NR¹⁴R¹⁵; R¹³ is halogen, —NO₂, —CN, —OH,(C₁-C₄)-alkyl, (C₁-C₄)-alkyloxy, —CF₃ or —NH₂; L is direct bond or(C₁-C₃)-alkylene; A is hydrogen, —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl,—C(O)—NR⁴R⁵ or (C₁-C₄)-alkyl; U is —NH₂, methyl,—NH—C(O)—O—(C₁-C₄)-alkyl or —NH—C(O)—O—(CH₂)-phenyl; M is hydrogen,(C₁-C₃)-alkyl- or —OH, and R⁴ and R⁵ are independently of one anotherhydrogen or (C₁-C₄)-alkyl.
 15. The compound according to claim 12,wherein R₀ is phenyl or pyridyl, wherein the phenyl and pyridyl areeach, independently, mono-, di- or trisubstituted independently of oneanother by R², R² is halogen, —CN, —(C₁-C₄)-alkyloxy, wherein thealkyloxy is unsubstituted or substituted by halogen or amino, or—(C₁-C₄)-alkyl, wherein the alkyl is unsubstituted or substituted by anamino or halogen; R₁₀ is hydrogen; X is —(C₁-C₃)-alkylene, wherein thealkylene is unsubstituted or mono-, di- or trisubstituted independentlyof one another by halogen, amino or hydroxy; the substructure of formulaIII is phenyl, wherein the phenyl is unsubstituted or mono-, di- ortrisubstituted independently of one another by R¹; D is carbon; R¹ ishalogen, —NO₂, —CN, —OH, —SO₂—NH₂, (C₁-C₄)-alkylamino-,(C₁-C₄)-alkyloxy, (C₁-C₄)-alkyl, or (C₁-C₄)-alkylsulfonyl-, wherein thealkyl is unsubstituted or mono-, di- or trisubstituted independently ofone another by R¹³, (C₆-C₁₄)-aryl, wherein the aryl is unsubstituted ormono-, di- or trisubstituted independently of one another by R¹³,—C(O)—NR¹⁴R¹⁵, or R¹¹R¹²N—; R¹³ is halogen, —CF₃, —NH₂, —OH,(C₁-C₄)-alkyl or (C₁-C₄)-alkyloxy; V is a fragment of the formula IIa,IIb, IIc or IId; L is direct bond or (C₁-C₂)-alkylene; A is hydrogen,—C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵ or (C₁-C₄)-alkyl; U is—NH₂, methyl, —NH—C(O)—O—(C₁-C₄)-alkyl or —NH—C(O)—O—(CH₂)-phenyl; M ishydrogen or (C₁-C₃)-alkyl-; and R⁴ and R⁵ are independently of oneanother hydrogen or methyl.
 16. The compound according to claim 12,wherein R₀ is phenyl, wherein the phenyl is mono-, di- or trisubstitutedindependently of one another by R², R² is halogen, —(C₁-C₄)-alkyloxy,wherein the alkyloxy is unsubstituted or substituted by halogen oramino, or —(C₁-C₄)-alkyl, wherein the alkyl is unsubstituted orsubstituted by an amino or halogen; R¹⁰ is hydrogen; X is—(C₁-C₃)-alkylene; the substructure of formula III is phenyl, whereinphenyl is unsubstituted or mono-, di- or trisubstituted independently ofone another by R¹; D is carbon; R¹ is halogen, —NO₂, —CN, —OH, —SO₂—NH₂,(C₁-C₄)-alkylamino-, (C₁-C₄)-alkyloxy, (C₁-C₄)-alkyl, or(C₁-C₄)-alkylsulfonyl-, wherein the alkyl is unsubstituted or mono-, di-or trisubstituted independently of one another by R¹³, —C(O)—NR¹⁴R¹⁵ orR¹¹R¹²N—; R¹³ is halogen, —CF₃, —NH^(2,) —OH, —(C₁-C₄)-alkyl, or—(C₁-C₄)-alkyloxy; R¹⁴ and R¹⁵ are, independently, hydrogen or(C₁-C₂)-alkyl-; V is a fragment of the formula IIa, IIb, IIc or IId; Lis direct bond or (C₁-C₂)-alkylene; A is hydrogen, —C(O)—OH,—C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵ or —(C₁-C₄)-alkyl; U is —NH₂, methyl,—NH—C(O)—O—(C₁-C₄)-alkyl or —NH—C(O)—O—(CH₂)-phenyl; M is hydrogen ormethyl; and R⁴ and R⁵ are independently of one another hydrogen ormethyl.
 17. The compound according to claim 12, wherein R₀ is phenyl,wherein the phenyl is disubstituted independently of one another by R²;R² is halogen, (C₁-C₂)-alkyloxy, wherein the alkyloxy is unsubstitutedor substituted by amino, or —(C₁-C₄)-alkyl, wherein the alkyl isunsubstituted or substituted by amino; R¹⁰ is hydrogen; X is —CH₂—CH₂—;the substructure of formula II is phenyl, wherein the phenyl isunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹; D is carbon; R¹ is halogen, —OH, —NH₂, —C(O)—NR¹⁴R¹⁵, or—(C₁-C₃)-alkyloxy, or —(C₁-C₃)-alkyl, wherein the alkyl is unsubstitutedor mono-, di- or trisubstituted independently of one another by R¹³; R¹⁴and R¹⁵ are, independently, hydrogen or (C₁-C₂)-alkyl-; R¹³ is fluorineor chlorine; V is a fragment of the formula IIa, IIb, IIc or IId; isdirect bond or (C₁-C₂)-alkylene, A is hydrogen, —C(O)—OH,—C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵ or —(C₁-C₄)-alkyl, U is —NH₂, methyl,—NH—C(O)—O—(C₁-C₄)-alkyl or —NH—C(O)—O—(CH₂)-phenyl, M is hydrogen, andR⁴ and R⁵ are independently of one another hydrogen or methyl.
 18. Aprocess for the preparation of a compound of the formula I as claimed inclaim 12, comprising a) linking a building block of the formula XI witha fragment of formula XII,

wherein R₀, Q, Q′ and X, are as defined in claim 12, R¹′, R¹″, R¹′″ andR¹′″ are each hydrogen or as R¹ as defined in claim 12, and Y is anucleophilically substitutable leaving group or a hydroxyl group,wherein R₀, R¹, and X can also be present in protected form or in theform of precursor groups, and wherein the formula XII isH—NR₁₀—V   (XII) wherein R₁₀ and V are as defined in claim 12, and canalso be present in protected form or in the form of precursor groups, orb) coupling of a fragment of formula XIII with a fragment of formulaXII,R₀-Q-X-Q′-W—C(O)—Y   (XII) wherein R₀, Q, Q′ and X, are as defined inclaim 12, W is the substructure of formula III, and Y is anucleophilically substitutable leaving group or a hydroxyl group,wherein R₀, R¹, and X can also be present in protected form or in theform of precursor groups.
 19. A pharmaceutical composition comprising atherapeutically effective amount of at least one compound according toclaim 12 and a pharmaceutically acceptable carrier.
 20. A method forinhibiting factor Xa comprising contacting an effective amount of thecompound according to claim 12 with factor Xa.
 21. A method forinhibiting factor VIIa comprising contacting an effective amount of thecompound according to claim 12 with factor VIIa.
 22. A method oftreating blood coagulation disorder in a host in need thereof comprisingadministering a therapeutically effective amount of the compoundaccording to claim 19 to the host.
 23. A method of treating inflammatoryresponse in a host in need thereof comprising administering atherapeutically effective amount of the compound according to claim 19to the host.
 24. A method of treating fibrinolysis in a host in needthereof comprising administering a therapeutically effective amount ofthe compound according to claim 19 to the host.
 25. A method of treatingrestenosis in a host in need thereof comprising administering atherapeutically effective amount of the compound according to claim 19to the host.
 26. The method of claim 25, wherein the restenosis occursas a result of at least one of angioplasty, coronary heart disease,adult respiratory distress syndrome, multi-organ failure, stroke, viralinfections, cancer or a disseminated intravascular clotting disorder.27. A method of treating transient ischemic attack in a host in needthereof comprising administering a therapeutically effective amount ofthe compound according to claim 19 to the host.
 28. A method of treatingthrombosis in a host in need thereof comprising administering atherapeutically effective amount of the compound according to claim 19to the host.
 29. The method of claim 28, wherein the thrombosis occursas a result of at least one of thrombolytic therapy, surgery, amyocardial infarction, angina, or stroke.